Cross-linking by epichlorohydrin and diepoxybutane correlates with cytotoxicity and leads to apoptosis in human leukemia (HL-60) cells

Le, Phuong M.; Silvestri, Vanesa L.; Redstone, Samuel C.; Dunn, Jordanne B.; Millard, Julie T.

doi:10.1016/j.taap.2018.05.020

Cited by 12 publications

(5 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Apoptosis, also known as programmed cell death, is a special type of cell death in the biological world [18]. Apoptosis activates the membrane signaling system and apoptotic procedural genes, and when it is induced by certain physiological or pathological factors, apoptosis ultimately leads to self-destruction and death of cells via certain processes [19]. Studies have shown that apoptosis is regulated by a series of genes can be divided into 2 groups based on their effects—apoptosis inhibitory factors and apoptosis promoting factors.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Tumor Protein p53-regulated Apoptosis-inducing Protein 1 Regulates Proliferation and Apoptosis of Breast Cancer Cells through the PI3K/Akt Pathway

2019

View full text Add to dashboard Cite

Purpose Tumor protein p53-regulated apoptosis-inducing protein 1 (TP53AIP1) functions in various cancers. We studied the effect and molecular mechanism of TP53AIP1 in breast cancer. Methods The degree of correlation between TP53AIP1 expression and overall survival in patients with breast cancer was obtained from the online The Cancer Genome Atlas database. Six of the TP53AIP1 levels in the tumor and adjacent non-tumor tissues randomly selected from 38 breast cancer patients were determined. Transgenic technology was used to enhance the expression of TP53AIP1 in breast cancer cell lines, MDA-MB-415 and MDA-MB-468, and to observe the effects of gene overexpression on the proliferation, cell cycle, and apoptosis of breast cancer cells. The molecular mechanism of association between cell cycle- and apoptosis-related factors and the phosphoinositide 3-kinases/protein kinase B (PI3K/Akt) pathway was also studied. Results The messenger RNA and protein expression levels of TP53AIP1 in cancer tissues were significantly lower than those in the control group. TP53AIP1 overexpression inhibits cell viability. The mechanism of TP53AIP1 inhibition of proliferation and growth of breast cancer cells includes cell cycle arrest, apoptosis promotion ( p < 0.01), promotion of the expression of cleaved-caspase-3 ( p < 0.01), cleaved-caspase-9 ( p < 0.01), B cell lymphoma/leukemia-2 (Bcl-2)-associated X protein, and p53 ( p < 0.01), and the inhibition of Bcl-2, Ki67, and PI3K/Akt pathways ( p < 0.01). Conclusion TP53AIP1 may be a novel tumor suppressor gene in breast cancer and can potentially be used as an effective target gene for the treatment of breast cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

Overexpression of Tumor Protein p53-regulated Apoptosis-inducing Protein 1 Regulates Proliferation and Apoptosis of Breast Cancer Cells through the PI3K/Akt Pathway

2019

View full text Add to dashboard Cite

show abstract

“…Here, cross-linked DNA migrates slowly as the round comet “head” whereas the small pieces of DNA generated by strand breaks yield the “tail.” Analyses were performed using Comet Assay Software Project. The cross-linking rate was calculated as the decrease in the percentage of olive tail moment (OTM) in cells treated with the indicated drugs and H 2 O 2 relative to cells treated with only H 2 O 2 . , The percentage decrease representing the level of ICLs in treated cells was calculated as follows: ( 1 − OTM drug + H 2 O 2 − OTM drug − OTM control OTM H 2 O 2 − OTM control ) × 100 where OTM control , OTM H 2 O 2 , OTM drug , and OTM drug+H 2 O 2 represent the OTMs of cells treated with neither drug nor H 2 O 2 , with only H 2 O 2 , with only drug, and with both drug and H 2 O 2 , respectively.…”

Section: Methodsmentioning

confidence: 99%

“…The crosslinking rate was calculated as the decrease in the percentage of olive tail moment (OTM) in cells treated with the indicated drugs and H 2 O 2 relative to cells treated with only H 2 O 2 . 44,45 The percentage decrease representing the level of ICLs in treated cells was calculated as follows: In Vivo Xenograft Studies. The in vivo antitumor effect of LND in combination with ACNU was evaluated in BALB/c nude mice (male, 8 weeks old) with resistant SF763 tumors.…”

Section: ■ Conclusionmentioning

confidence: 99%

Energy Blocker Lonidamine Reverses Nimustine Resistance in Human Glioblastoma Cells through Energy Blockade, Redox Homeostasis Disruption, and O⁶-Methylguanine-DNA Methyltransferase Downregulation: In Vitro and In Vivo Validation

Huang,

Wang,

Fan

et al. 2024

ACS Pharmacol. Transl. Sci.

View full text Add to dashboard Cite

Tumor resistance seriously hinders the clinical application of chloroethylnitrosoureas (CENUs), such as O 6methylguanine-DNA methylguanine (MGMT), which can repair O 6 -alkyl lesions, thereby inhibiting the formation of cytotoxic DNA interstrand cross-links (ICLs). Metabolic differences between tumor and normal cells provide a biochemical basis for novel therapeutic strategies aimed at selectively inhibiting tumor energy metabolism. In this study, the energy blocker lonidamine (LND) was selected as a chemo-sensitizer of nimustine (ACNU) to explore its potential effects and underlying mechanisms in human glioblastoma in vitro and in vivo. A series of cell-level studies showed that LND significantly increased the cytotoxic effects of ACNU on glioblastoma cells. Furthermore, LND plus ACNU enhanced the energy deficiency by inhibiting glycolysis and mitochondrial function. Notably, LND almost completely downregulated MGMT expression by inducing intracellular acidification. The number of lethal DNA ICLs produced by ACNU increased after the LND pretreatment. The combination of LND and ACNU aggravated cellular oxidative stress. In resistant SF763 mouse tumor xenografts, LND plus ACNU significantly inhibited tumor growth with fewer side effects than ACNU alone. Finally, we proposed a new "HMAGOMR" chemo-sensitizing mechanism through which LND may act as a potential chemo-sensitizer to reverse ACNU resistance in glioblastoma: moderate inhibition of hexokinase (HK) activity (H); mitochondrial dysfunction (M); suppressing adenosine triphosphate (ATP)-dependent drug efflux (A); changing redox homeostasis to inhibit GSH-mediated drug inactivation (G) and increasing intracellular oxidative stress (O); downregulating MGMT expression through intracellular acidification (M); and partial inhibition of energy-dependent DNA repair (R).

show abstract

“…[ 1,4–7 ] DEB induces oxidative stress, DNA lesions, protein crosslinks, intra‐strand and interstrand DNA–DNA crosslinks, and apoptosis. [ 8–15 ] The molecular mechanisms of BD and DEB‐induced toxicity are not completely understood.…”

Section: Introductionmentioning

confidence: 99%

Diepoxybutane induces the p53‐dependent transactivation of the CCL4 gene that mediates apoptosis in exposed human lymphoblasts

Ewunkem

Deve

Harrison

et al. 2023

J Biochem & Molecular Tox

View full text Add to dashboard Cite

Diepoxybutane (DEB) is the most toxic metabolite of the environmental chemical 1,3-butadiene. We previously demonstrated the occurrence of DEB-induced p53mediated apoptosis in human lymphoblasts. The p53 protein functions as a master transcriptional regulator in orchestrating the genomic response to a variety of stress signals. Transcriptomic analysis indicated that C-C chemokine ligand 4 (CCL4) gene expression was elevated in a p53-dependent manner in DEB-exposed p53-proficient TK6 cells, but not in DEB-exposed p53-deficient NH32 cells. Thus, the objective of this study was to determine whether the CCL4 gene is a transcriptional target of p53 and deduce its role in DEB-induced apoptosis in human lymphoblasts. Endogenous and exogenous wild-type p53 transactivated the activity of the CCL4 promoter in DEB-exposed lymphoblasts, but mutant p53 activity on this promoter was reduced by ∼80% under the same experimental conditions. Knockdown of the upregulated CCL4 mRNA levels in p53-proficient TK6 cells inhibited DEB-induced apoptosis by ∼45%-50%. Collectively, these observations demonstrate for the first time that the CCL4 gene is upregulated by wild-type p53 at the transcriptional level, and this upregulation mediates apoptosis in DEB-exposed human lymphoblasts.

show abstract

Cross-linking by epichlorohydrin and diepoxybutane correlates with cytotoxicity and leads to apoptosis in human leukemia (HL-60) cells

Cited by 12 publications

References 61 publications

Overexpression of Tumor Protein p53-regulated Apoptosis-inducing Protein 1 Regulates Proliferation and Apoptosis of Breast Cancer Cells through the PI3K/Akt Pathway

Overexpression of Tumor Protein p53-regulated Apoptosis-inducing Protein 1 Regulates Proliferation and Apoptosis of Breast Cancer Cells through the PI3K/Akt Pathway

Energy Blocker Lonidamine Reverses Nimustine Resistance in Human Glioblastoma Cells through Energy Blockade, Redox Homeostasis Disruption, and O⁶-Methylguanine-DNA Methyltransferase Downregulation: In Vitro and In Vivo Validation

Diepoxybutane induces the p53‐dependent transactivation of the CCL4 gene that mediates apoptosis in exposed human lymphoblasts

Contact Info

Product

Resources

About

Cross-linking by epichlorohydrin and diepoxybutane correlates with cytotoxicity and leads to apoptosis in human leukemia (HL-60) cells

Cited by 12 publications

References 61 publications

Overexpression of Tumor Protein p53-regulated Apoptosis-inducing Protein 1 Regulates Proliferation and Apoptosis of Breast Cancer Cells through the PI3K/Akt Pathway

Overexpression of Tumor Protein p53-regulated Apoptosis-inducing Protein 1 Regulates Proliferation and Apoptosis of Breast Cancer Cells through the PI3K/Akt Pathway

Energy Blocker Lonidamine Reverses Nimustine Resistance in Human Glioblastoma Cells through Energy Blockade, Redox Homeostasis Disruption, and O6-Methylguanine-DNA Methyltransferase Downregulation: In Vitro and In Vivo Validation

Diepoxybutane induces the p53‐dependent transactivation of the CCL4 gene that mediates apoptosis in exposed human lymphoblasts

Contact Info

Product

Resources

About

Energy Blocker Lonidamine Reverses Nimustine Resistance in Human Glioblastoma Cells through Energy Blockade, Redox Homeostasis Disruption, and O⁶-Methylguanine-DNA Methyltransferase Downregulation: In Vitro and In Vivo Validation